Abstract Idiopathic focal segmental glomerulosclerosis (FSGS) is a proteinuric glomerular disease, which disproportionately affects racial minorities, and is caused by injury to the glomerular epithelial cell. Treatment often fails to stop progressive loss of kidney function, reflecting our incomplete understanding of pathogenic mechanisms. While some etiologies of FSGS are known, none can be identified for FSGS in many patients. Viral infection may cause FSGS for the following reasons. First, viral infections can cause kidney diseases. Replicating HIV-1 has been demonstrated in kidney tissue of patients with HIV-associated nephropathy (HIVAN), another form of FSGS. Second, polymorphisms in the APOL1 gene, which encodes an innate immune effector molecule, are present only in individuals of recent African ancestry and strongly associate with HIVAN and idiopathic FSGS in African American patients. Given these similarities in pathology and genetic susceptibility, we hypothesize idiopathic FSGS also is caused by infection of kidney cells by an unknown virus in susceptible subjects who have the APOL1 high risk genotype. As an exploratory project, we plan to identify candidate viral sequences within the transcriptomes of the glomerular and tubulointerstitial compartments microdissected from kidney biopsies from 164 FSGS subjects in the NIH-funded NEPTUNE cohort. These individuals have deep phenotyping data (clinical, genomic and pathological) and renal biopsies that have been processed for RNA analysis. Using state-of-the-art, high throughput sequencing methods, we will generate kidney biopsy RNAseq data and analyze these with an established bioinformatic pipeline to discover nucleic acid signatures of viruses which associate with FSGS in subjects with APOL1 high risk genotypes. Kidney biopsies are available from subjects to replicate positive results and serve as negative controls. If our hypothesis is true, these results will be paradigm shifting in our understanding of chronic kidney disease, and would have a great clinical impact on diagnosis (non-invasive testing), prevention (vaccine development), and treatment (use of anti-viral therapy) of FSGS.